The overall aim of this project is to evaluate the feasibility of using a novel gemcitabine-ibandronate conjugate alone and/or as part of a combination therapy for the treatment of osteosarcoma and associated metastases. The conjugate consists of chemically linked anticancer antimetabolite Gemcitabine and the bone-homing bisphosphonate Ibandronate. The novel conjugate directly addresses the limitations of conventional osteosarcoma therapies by concentrating drug at the site of bone lesions and offers potential improvements in efficacy and side-effect profiles. This targeted delivery design provides for an effective concentration of a chemotherapy agent in bone while maintaining low systemic levels. As such, we hypothesize that this conjugate will have a wider therapeutic range and offer the potential for synergies with other drugs as compared to currently available therapies. As an added benefit, the drug is anticipated to strengthen the bones and may reverse the deterioration of bone associated with bony malignancies. This project looks specifically at the ability of the Gemcitabine-Ibandronate conjugate alone or in combination with Docetaxel to demonstrate improved benefits in treating a mouse model of osteosarcoma as compared to treatment with free Gemcitabine in combination with Docetaxel. The specific aims of this Phase I project is to assess the effects of the novel bone targeting conjugate-alone and in combination with Docetaxel on local tumor burden, bone lysis and metastatic burden in an orthotopic osteosarcoma syngeneic murine model. The successful completion of this project will guide the further development of this promising drug design concept and will ultimately result in therapeutic agents that will significantly improve cancer patient care, resulting in increased quality of life and survival.